DISCUSSION

We have observed no difference produced in the improvement in PEFR over a 150-minute period in three groups of patients with acute asthma treated with inhaled salbutamol and ipratropium bromide given sequentially or in combination. It is possible that a type 2 error has occurred to account for the failure to show any difference between the groups. At 150 minutes, this study had a power of 80 percent to detect a difference of 63 L/min between the groups; in order to detect a 25 L/min difference at the 80 percent level, 170 patients in each group would be needed. These figures imply that, if such a difference exists between the treatment groups, the study would detect the difference eight times out of ten. This suggests one of three alternative explanations for our results; either the lack of difference in treatment effect between the three groups is a real phenomenon, or that if the study were to be repeated, the difference would be detected, or that the difference in treatments is too small to be detected with the numbers of subjects used.

This is the largest single-center study of its type of which we are aware and serves to highlight the difficulties inherent in performing such a study in order to detect relatively small treatment differences between groups. More importantly, if a difference does exist between these treatments, it is small, implying that one would need to treat many patients with both drugs in order to benefit a few.

Our results were not influenced by differential treatment with corticosteroids between the three groups. The clinical effect of steroids is not detectable earlier than three to six hours. Therefore, patients who received steroids at the commencement of our study would be unlikely to show any resulting effect within the period of study. levitra plus

Ipratropium contains the preservatives benzalkonium and EDTA which have been shown to be bronchoconstrictor for a proportion of asthmatic pa­tients. Our measured peak flow changes following ipratropium may reflect, in part, a bronchoconstrictor effect in the patients whom we studied. However, salbutamol also contains preservatives (oral commu­nication, 1988, Glaxo Australia), which are present in similar concentration to those in ipratropium. Our data suggest that ipratropium is an effective broncho- dilator when given as the first agent. It is difficult to hypothesize that the additives have a confounding effect selectively upon ipratropium but not salbuta­mol, and that the confounding effect occurs when the drug is given second but not when given first. In group C, who received ipratropium second, there is a fall in PEFR between 75 and 120 minutes. This may reflect the waning effect of salbutamol given at time 0, alone, or combined with lack of bronchodilator effect of ipratropium in these patients.

In agreement with previous studies, we have shown that ipratropium, when given alone as the first drug, is an effective bronchodilator. However, we have not found it to be superior to a placebo when placebo was administered following salbutamol and ipratropium in combination. We are unable to draw any definitive conclusion as to the place of ipratropium, since our study was not designed to compare ipratropium and placebo. The conflict between our findings and those of previous workers may relate to the different design of our study.

First, we report a substantially larger number of patients than previous studies, with the single excep­tion of one report including patients from four centers.The remaining studies comprise substantially fewer (12 to 40 per study) patients than we report here.
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Second, our trial design has a placebo in one arm of the study. This permits comparison between pla­cebo, ipratropium, and salbutamol all given as the second nebulized preparation. A true control group, which received no treatment, is not ethical in an acute and potentially fatal medical condition. However, inclusion of a placebo as second treatment following an active treatment given first in one arm of a double- blind controlled study, considerably enhances the interpretation of our results. None of the previous reports had a placebo in its design.